Context Consumption of red and processed meat has been associated with colorectal
cancer in many but not all epidemiological studies; few studies have examined
risk in relation to long-term meat intake or the association of meat with
rectal cancer.

Objective To examine the relationship between recent and long-term meat consumption
and the risk of incident colon and rectal cancer.

Design, Setting, and Participants A cohort of 148 610 adults aged 50 to 74 years (median, 63 years),
residing in 21 states with population-based cancer registries, who provided
information on meat consumption in 1982 and again in 1992/1993 when enrolled
in the Cancer Prevention Study II (CPS II) Nutrition Cohort. Follow-up from
time of enrollment in 1992/1993 through August 31, 2001, identified 1667 incident
colorectal cancers. Participants contributed person-years at risk until death
or a diagnosis of colon or rectal cancer.

Results High intake of red and processed meat reported in 1992/1993 was associated
with higher risk of colon cancer after adjusting for age and energy intake
but not after further adjustment for body mass index, cigarette smoking, and
other covariates. When long-term consumption was considered, persons in the
highest tertile of consumption in both 1982 and 1992/1993 had higher risk
of distal colon cancer associated with processed meat (RR, 1.50; 95% confidence
interval [CI], 1.04-2.17), and ratio of red meat to poultry and fish (RR,
1.53; 95% CI, 1.08-2.18) relative to those persons in the lowest tertile at
both time points. Long-term consumption of poultry and fish was inversely
associated with risk of both proximal and distal colon cancer. High consumption
of red meat reported in 1992/1993 was associated with higher risk of rectal
cancer (RR, 1.71; 95% CI, 1.15-2.52; P = .007
for trend), as was high consumption reported in both 1982 and 1992/1993 (RR,
1.43; 95% CI, 1.00-2.05).

Conclusions Our results demonstrate the potential value of examining long-term meat
consumption in assessing cancer risk and strengthen the evidence that prolonged
high consumption of red and processed meat may increase the risk of cancer
in the distal portion of the large intestine.

Meat consumption has been associated with colorectal neoplasia in the
epidemiological literature, but the strength of the association and types
of meat involved have not been consistent. Few studies have evaluated long-term
meat consumption or the relationship between meat consumption and the risk
of rectal cancer. Studies of red meat consumption and colorectal adenoma have
reported odds ratios in the range of 1.2 to 1.3.1-3 Case-control
studies4-25 of
colorectal cancer conducted in the United States and Europe have generally
reported increased risk associated with red or processed meat intake in analyses
of men,4-9,13,14 and
men and women combined,10-12,15-25 but
not in analyses that included only women.5-9,13 Case-control
studies26-32 of
colorectal cancer among Asians in the United States or Asia have more consistently
reported a positive association with red, processed, or total meats.

Five33-37 of
1033-42 US
prospective studies of colorectal cancer reported positive associations with
red or processed meat intake, although some associations35-37 did
not reach statistical significance. European prospective studies43-49 have
generally reported no association with fresh or total meat but positive associations
with cured or processed meat,43,45,46 sausages,47 or smoked/salted fish.45 High
consumption of poultry or fish has been inconsistently associated with higher36,37,46 or lower34,40,41,47,49 risk
of colorectal cancer; some studies have found no association.33,39,42,43,45,48 Only
2 prospective studies38,49 have
reported on rectal cancer in relation to meat consumption. The results were
conflicting but were limited by the small number of cases.

A meta-analysis50 of case-control and
prospective studies estimated the mean relative risk comparing the highest
to lowest categories of meat consumption to be 1.35 (95% confidence interval
[CI], 1.21-1.51) for red meat and 1.31 (95% CI, 1.13-1.51) for processed meat
and colorectal cancer. A review of prospective studies51 concluded
that a daily increment of 100 g of red or total meat consumption was associated
with a 12% to 17% higher risk of colorectal cancer, and that an increment
of 25 g of processed meat was associated with a 49% higher risk. Not all risk
estimates included in these review articles were adjusted for potential confounders
beyond age and energy intake, so residual confounding may influence the summary
risk estimates.

Clarifying the role of meat consumption in colorectal carcinogenesis
is important. Meat is an integral component of diet in the United States and
many other countries in which colorectal cancer is common. Per capita annual
consumption of beef has increased in the United States since 1993, reversing
a previous decrease since 1976. Poultry consumption has surpassed beef consumption
since the late 1980s.52,53

An earlier analysis of the Cancer Prevention Study II (CPS II) Mortality
Cohort, based on deaths from colorectal cancer from 1982 to August 1988, found
no association between colorectal cancer mortality and high consumption of
red meat, but suggested lower risk associated with higher intake of chicken
and fish in women.41 We examined the relationship
between meat consumption and incident colon and rectal cancers among 148 610
men and women enrolled in the CPS II Nutrition Cohort in 1992/1993.

Methods

Study Population

The CPS II Nutrition Cohort has been described in detail elsewhere.54 Briefly, the CPS II Nutrition Cohort comprised 86 404
men and 97 786 women who completed a mailed questionnaire in 1992/1993
and were followed up for cancer incidence and mortality. This cohort is a
subset of the CPS II Mortality Cohort in which 1.2 million US adults from
all 50 states, Puerto Rico, and the District of Columbia have been followed
up for cancer mortality since 1982.54 In the
CPS II Mortality Cohort, participants completed a self-administered questionnaire
in 1982 with information on diet, exercise, medical history, and other lifestyle
habits. Race was determined on this 1982 questionnaire by multiple choice
(white, black, Hispanic, Oriental, and other). Enrollment in the CPS II Nutrition
Cohort was limited to men and women aged 50 to 74 years, residing in 21 states
with population-based cancer registries that demonstrated at least 90% ascertainment
of incident cancers by 1990. The median age at the CPS II Nutrition Cohort
enrollment was 63 years.

The 1992/1993 CPS II Nutrition Cohort questionnaire obtained information
on diet, physical activity, medical history, and other lifestyle habits. This
cohort was recontacted at 2-year intervals between 1997 and 2003 with self-administered
questionnaires to update information on newly diagnosed cancers, medical history,
and lifestyle factors. Reported cancer diagnoses through 2001 have been verified
by clinical information obtained from medical records or linkage with state
cancer registries. An earlier study linking CPS II Nutrition Cohort participants
to state cancer registries demonstrated that self-report of any cancer could
identify incident cancers with a sensitivity of 93%.55 Mortality
follow-up of the entire CPS II Nutrition Cohort54 is
ongoing through automated linkage with the National Death Index. Cohort participants
on average report higher educational attainment and more behaviors suggesting
health consciousness than the general US population.54 Participants
were informed of data linkage activities on each mailed questionnaire and
provided written consent by returning the completed questionnaire. All aspects
of the CPS II study protocol were approved by the Emory University Institutional
Review Board.

This analysis was based on 1667 incident cases of colon or rectal cancer
diagnosed from the time of enrollment in 1992/1993 through August 31, 2001.
Participants contributed person-years at risk until death or a diagnosis of
colon or rectal cancer. Excluded from the analysis were persons who were not
known to be deceased but failed to respond to the 1997, 1999, and 2001 questionnaires
(3.7%); reported a colon or rectal cancer not verified by pathology report
or death certificate (0.3%); reported at baseline a personal history of colon
or rectal cancer (1.5%); reported uninterpretable or missing data on meat
consumption in 1982 (4.7%); completed less than 85% of the food section of
the 1992/1993 questionnaire; or reported implausibly high or low energy intake
(9.1%). After exclusions, the analytic cohort included 69 664 men and
78 946 women, representing 81% of the CPS II Nutrition Cohort.

Incident Colon and Rectal Cancer

A total of 1197 incident cancers of the colon (International Classification
of Diseases codes: C18.0, C18.2-C18.9)56,57 and
470 cancers of the rectosigmoid junction (C19.0)56,57 or
rectum (C20.9)56,57 were identified.
Of these, 665 colon and 291 rectal cancers were diagnosed in men, and 532
colon and 179 rectal cancers in women. A total of 1335 (80%) of 1667 colorectal
cancers were self-reported on the 1997, 1999, or 2001 questionnaires and subsequently
verified by medical record abstraction or linkage with state cancer registries;
another 43 (3%) were identified while verifying a different reported cancer;
and 289 (17%) were identified as interval deaths, defined as persons who died
with colon or rectal cancer recorded on death certificate but not reported
on the questionnaire. Linkage with state cancer registries confirmed the diagnosis
of colon or rectal cancer in 74% of interval deaths. Subsite-specific analyses
were conducted on 667 proximal (cecum to splenic flexure) and 408 distal (descending
to sigmoid colon) colon cancers, excluding those with overlapping or unspecified
site codes. We also present the results from analyses of 470 cancers of the
rectosigmoid and rectum combined but not from separate analyses of the rectosigmoid
junction (214 cases) or rectum (246 cases). The remaining 10 cases were unspecified
(not able to distinguish as rectum or rectosigmoid junction).

Meat Consumption

Dietary assessment in 1992/1993 was based on a 68-item modified Block58 food-frequency questionnaire (FFQ); nutrient values
were estimated using the Dietary Analysis System version 3.8a.59 Participants
were asked to report their usual eating habits during the past year, including
average frequency and serving size (small, medium, or large) of each food
and beverage listed. Consumption of each meat item in grams per week was estimated
by taking the product of average frequency per week, number of grams in a
medium serving, and serving size (0.5 for small, 1.0 for medium, and 1.5 for
large). Intake of red meat, poultry and fish, and processed meat (g/wk) was
computed by summing across meat items that contributed to each meat group
and categorizing by quintile. The lowest quintile of intake served as the
referent group for analyses.

We considered red meat to include the following individual or grouped
items on the questionnaire: bacon; sausage; hamburgers, cheeseburgers, meatloaf,
or casserole with ground beef; beef (steaks, roasts, etc, including sandwiches);
beef stew, or pot pie with carrots or other vegetables; liver, including chicken
livers; pork, including chops, roast; hot dogs; and ham, bologna, salami,
or lunchmeat. Food items classified as poultry and fish included chicken or
turkey (roasted, stewed, broiled, ground, including sandwiches); fried chicken;
fried fish or fish sandwich; tuna, tuna salad, tuna casserole; and other fish
(broiled or baked). We considered processed meat to include bacon; sausage;
hot dogs; and ham, bologna, salami, or lunchmeat. We computed the ratio of
red meat-to-poultry and fish by dividing red meat intake by intake of poultry
and fish (g/wk); individuals were assigned to the lowest or highest quintile
when either value was 0. An additional question, “How often did you
eat beef, pork, or lamb as a main dish, eg, steak, roast ham, etc (4-6 ounces)?”
was included for comparison with other studies that included this question.
Participants were also asked, “When you eat red meat such as beef, pork,
or lamb, how well done is it cooked?” with the following possible responses
on the questionnaire, “well-done, medium well done, medium rare, rare,
and don’t eat red meat.”

The 1992/1993 FFQ was validated among 441 Nutrition Cohort members who
completed four 24-hour dietary recall interviews and a repeat FFQ.60 For red meat, the correlation coefficient between
the FFQ and dietary recall interview was 0.55 among men and 0.78 in women;
between the initial FFQ and the repeat FFQ, the correlation coefficient was
0.81 in men and 0.78 in women.

The 1982 questionnaire asked participants to report the average number
of days per week they ate each of the 11 meat items. Intake frequencies of
red meat, poultry and fish, and processed meat were computed by summing the
number of days per week across individual meat items that contributed to each
meat group, and categorizing into quintiles. Foods categorized as red meat
were beef, pork, ham, liver, smoked meats, frankfurters/sausage, fried bacon,
and fried hamburger; poultry and fish included chicken, fish, and fried chicken/fish;
and processed meats included ham, smoked meats, frankfurters/sausage, and
fried bacon. Turkey was not included on the 1982 questionnaire but was included
on the 1992/1993 questionnaire.

We examined long-term meat consumption by considering consumption reported
in 1982 and in 1992/1993. Consumption at each time point was categorized into
tertiles (low, moderate, high) and participants were classified as low intake
in 1982 and 1992/1993 (referent group), high intake in 1982 and 1992/1993,
and all other combinations of intake over time.

Statistical Analysis

Colon and rectal cancer incidence rate ratios (RRs) and 95% CIs by meat
intake were estimated using Cox proportional hazards regression modeling. P values for linear trend were estimated by modeling meat
intake (g/wk) using the median value within quintiles; these results were
similar when modeled as continuous variables. This study was observational,
not randomized, so P values were interpreted as approximate.61 To obtain P values and confidence
limits, we treated the disease outcome as though it were a random variable
that changed over time. Potential confounders were chosen based on a priori
considerations and on the observed association with colon or rectal cancer
and meat intake.

For each meat variable, we constructed 3 models stratified by single
year of age, controlling for other covariates. Model 1 also included total
energy (continuous); model 2 included total energy, education (some high school,
high school graduate, some college or trade school, college graduate or postgraduate
work, or unknown), body mass index calculated as weight in kilograms divided
by the square of height in meters in 1992/1993 (<18.5, 18.5-24.9, 25.0-29.9,
30.0-39.9, ≥40.0, or unknown), cigarette smoking in 1992/1993 (never, former,
current, ever smoker not specified, or unknown), recreational physical activity
in 1992/1993 (none, hours per week of walking, or walking plus other activities),
multivitamin use in 1982 (none, current user, or unknown), aspirin use in
1982 and in 1992 (nonuser in 1982 and 1992, ≥15 days per month in 1982
and 1992, <15 days per month in 1982 or 1992, or unknown at either time
point), intake of wine (none, any), beer (none, any), and liquor (none, any),
and hormone therapy use in 1992/1993 among women (nonuser, former user, current
user, ever user not specified, or unknown). Model 3 included all covariates
in model 2 plus intake of fruits in 1992/1993 (quintiles), vegetables in 1982
(quintiles), and high-fiber grain foods in 1982 (quintiles). Models of men
and women combined also included a term for sex. Family history of colorectal
cancer reported in 1982 was examined and excluded as a potential confounder;
no information on family history of colorectal cancer was available in 1992/1993.
Results of models including age and energy were similar to those from models
including only age or age plus energy in quintiles. In a subanalysis of meat
consumption reported in 1992/1993, we examined quintiles of energy-adjusted
intake of red meat, poultry and fish, and processed meat based on the residual
method.62 We also examined how the association
with each type of meat was affected when controlling for other types of meat;
no substantial difference was observed in these analyses (results not shown).

We tested the proportional hazard assumption for each meat intake variable
in relation to colon or rectal cancer using the likelihood ratio test, comparing
models with and without product terms for meat consumption (quintiles) and
follow-up time (years). We evaluated effect modification of the RR for colon
and rectal cancer in relation to meat consumption by other covariates using
the likelihood ratio test comparing models with and without interaction terms.
The Wald statistic was used to test for homogeneity of the RR for proximal
and distal colon cancers.63 All P values were 2-sided and considered significant at P<.05. All analyses were conducted using SAS version 9.0 (SAS Institute
Inc, Cary, NC).

Results

Participant Characteristics by Meat Consumption

Men and women reported a wide range in consumption of red and processed
meat in 1992/1993. A 10-fold difference was observed between the lowest and
highest quintiles of red meat in men and a 17-fold difference in women (Table 1). Men reported greater consumption of
red and processed meat than did women; median intake was 427 g/wk and 274
g/wk for red meat among men and women, respectively, and 95 g/wk and 43 g/wk
for processed meat, respectively. There was little variation in the consumption
of poultry and fish by quintiles of red meat intake. Men also reported substantially
higher intake of red and processed meats in 1982 than did women (data not
shown). Approximately half of the men and women in the top tertile for consumption
of red or processed meat in 1982 were also in the highest tertile in 1992/1993
(data not shown). The absolute levels of meat consumption in 1982 could not
be compared with consumption in 1992/1993 due to differences in the questionnaires.

Men and women who reported higher intake of red meat in 1992/1993 (Table 1) were more likely to report lower educational
attainment, no recreational physical activity, higher body mass index, current
cigarette smoking, beer and liquor drinking, higher total daily energy intake,
low fruit intake in 1992/1993, and little or no intake of vegetables or high-fiber
grain foods in 1982 compared with those with lower red meat intake. Men and
women who reported lower red meat intake tended to report multivitamin use
in 1982, wine drinking, and (in women) use of hormone therapy in 1992/1993.

Meat Consumption and Colon Cancer Incidence

Table 2 shows the relationship
between colon cancer incidence and meat consumption as reported in 1992/1993.
Higher intake of red and processed meat was associated with higher colon cancer
risk in men and women in models that adjusted only for age and energy intake
(model 1). However, the positive associations were attenuated in analyses
(model 2) that further adjusted for nondietary factors, including education,
body mass index, cigarette smoking, recreational physical activity, use of
multivitamins or aspirin, and (in women) use of hormone therapy. Further adjustment
for dietary factors (model 3) had little effect on the RR estimates. No association
was observed between colon cancer incidence and consumption frequency of beef,
pork, or lamb as a main dish, or with reported preference for red meat doneness
(data not shown).

Higher consumption of poultry and fish was inversely associated with
colon cancer risk in women but not men (Table
2). Further adjustment for additional covariates other than energy
attenuated the association. Among women, the inverse relationship remained
statistically significant (P = .03 for
trend). The positive association between colon cancer risk and ratio of red
meat-to-poultry and fish intake was also stronger in women than men. The trend
test for the ratio of red meat-to-poultry and fish intake was statistically
significant in men, women, and both sexes combined. The inverse, marginally
significant, association between high consumption of poultry and fish and
colon cancer risk in men and women remained unchanged when adjusting simultaneously
for red meat (data not shown).

Proximal and Distal Colon Cancer, and Rectal Cancer

Table 3 shows the relationship
between meat consumption reported in 1992/1993 and incident colon cancer by
subsite and rectal cancer in men and women combined. After covariate adjustment,
no consistent association was observed between consumption of red meat, poultry
and fish, or processed meat as reported at a single time point and cancer
of either subsite of the colon. Men and women in the second to fifth quintiles
of red meat intake had higher risk of rectal cancer compared with those in
the lowest quintile, particularly those individuals in the highest quintile
(RR, 1.71; 95% CI, 1.15-2.52; P = .007
for trend). This association was observed primarily with cancers of the rectosigmoid
junction (RR, 2.40; 95% CI, 1.30-4.43) with risk increasing significantly
with the amount of red meat consumed (P = .002
for trend). No significant association was observed between red meat consumption
and cancers of the rectum (data not shown). No clear association was observed
between rectal cancer risk and other measures of meat consumption reported
in 1992/1993.

Energy-Adjusted Meat Intake

Analyses using energy-adjusted meat intake reported in 1992/1993 yielded
results similar to those using meat intake (g/wk) with few exceptions. Compared
with risk estimates derived from nonenergy-adjusted meat intake, the association
between colon cancer and consumption of processed meat (RR, 1.35; 95% CI,
1.04-1.77; highest to lowest quintile, P = .02
for trend) became stronger in men, although the association between rectal
cancer and red meat intake (RR, 1.31; 95% CI, 0.96-1.79; P = .03 for trend) was attenuated in men and women combined.
Other risk estimates for red meat, poultry and fish, and processed meat remained
unchanged.

Long-term Meat Consumption

Table 4 presents multivariate-adjusted
RRs for colon cancer by subsite and rectal cancer among persons who were in
the highest tertile of meat consumption in both 1982 and 1992/1993 compared
with those in the lowest tertile at both time points. Prolonged high consumption
of red meat was associated with a statistically nonsignificant increased risk
of distal colon cancer (RR, 1.29; 95% CI, 0.88-1.89). The most consistent
associations were observed between distal colon cancer and prolonged high
intake of processed meat (RR, 1.50; 95% CI, 1.04-2.17), and ratio of red meat
to poultry and fish (RR, 1.53; 95% CI, 1.08-2.18) compared with persons with
prolonged low intake. These associations were not observed with cancer of
the proximal colon. The association between distal colon cancer and consumption
of processed meat was stronger in analyses based on long-term consumption
than on that reported only in 1982 (data not shown). Long-term high intake
of poultry and fish was marginally associated with lower risk of proximal
(RR, 0.77; 95% CI, 0.59-1.02) and distal (RR, 0.70; 95% CI, 0.50-0.99) colon
cancer.

Red meat consumption was marginally associated with higher risk of rectal
cancer (RR, 1.43; 95% CI, 1.00-2.05); this association was somewhat stronger
for cancers of the rectosigmoid junction (RR, 1.75; 95% CI, 1.04-2.96) than
for cancer of the rectum (RR, 1.31; 95% CI, 0.79-2.15). The relationship between
long-term consumption of red meat, poultry and fish, and risk of colon or
rectal cancer remained unchanged when all were included in the same model
(data not shown).

Effect Modification

No statistically significant interaction was observed between meat consumption
and other known risk factors for colon or rectal cancer on a multiplicative
scale.

Comment

The association between processed meat consumption and colon cancer
risk was independent of other covariates only when intake was measured at
2 time points during a 10-year interval. Moreover, the association was observed
consistently only for cancers of the distal colon. Prolonged high consumption
of red meat was associated with higher risk of rectal cancer, particularly
cancers of the rectosigmoid junction. Prolonged high consumption of poultry
and fish was marginally associated with lower risk of proximal and distal
colon cancer but not rectal cancer.

A strength of our study was the ability to control for several factors
known to influence colon cancer risk. Inadequate control for potential confounding
may partly explain the inconsistently observed positive associations between
red meat and colon cancer risk in other studies, since some positive articles
included in the quantitative reviews50,51 have
adjusted for only age and energy. In our analyses, the association between
colon cancer risk and high intake of red (RR, 1.41; 95% CI, 1.12-1.78) and
processed meat (RR, 1.33; 95% CI, 1.08-1.64) measured at a single time point
is consistent with meta-analysis results,50 adjusting
for age and energy intake. However, the association was substantially attenuated
with further adjustment for educational attainment, cigarette smoking, physical
activity, and other lifestyle factors associated with red meat intake.

To our knowledge, no study has addressed the relationship between long-term
meat consumption and risk of colon and rectal cancer. The association with
distal colon cancer was stronger among persons who reported greater consumption
of processed meat at 2 time points during a 10-year interval, as was the risk
of cancer of the rectosigmoid junction among those persons who consistently
reported high red meat intake. It is possible that true high consumers of
red or processed meat were better defined with less measurement error when
assessed twice during a 10-year period. It is also plausible that long-term
high consumption of red and processed meat may be more strongly associated
with colorectal carcinogenesis than short-term or sporadic consumption of
meat. Certain components of red meat may affect both early and late stages
in the development of neoplasia. Animal studies show that diets high in red
meat tend to affect the early aberrant crypt stage of carcinogenesis.64 To our knowledge, no study has evaluated the importance
of continued high exposure to red meat in animal models.

The higher risk associated with prolonged consumption of red meat but
not poultry and fish is consistent with other epidemiological studies.33,34,38,40 The
cytotoxic effect of dietary heme has been proposed as a potential mechanism
by which red meat increases colorectal cancer risk because of higher heme
content in red meat compared with poultry and fish.65,66 Heme
damages the colonic mucosa and stimulates epithelial proliferation in animal
studies.66 Both ingestion of red meat and heme
iron supplementation have been shown to increase fecal concentrations of N-nitroso compounds65 and
DNA-adducts in human colonocytes.67,68

We found that consistently high consumption of processed meat was associated
with increased risk of distal colon cancer. Results of prospective studies
of colorectal cancer and processed meat have been more consistently positive
in Europe43,45,47 than
in the United States.33,34,39,40,42 Processed
meat includes foods preserved by salting, smoking, or the addition of nitrites
or nitrates, and high consumption of these foods can increase exposure to
nitrosamines and their precursors. The amount of these substances in processed
meat likely varied by region and over time but we had no information to assess
the impact of these differences in our study results.

Several prospective studies have reported an inverse association between
colon cancer risk and prolonged high consumption of poultry and fish.34,40,41,47,49 However,
other studies have found either no association33,39,42,43,45,48 or
increased risk36,37,46 associated
with poultry and fish consumption. The lower risk associated with high consumption
of poultry and fish or a low ratio of red meat-to-poultry and fish could be
attributed to a displacement of red meat in the diet, but in our study high
consumption of poultry and fish remained independently associated with lower
risk of colon cancer even when controlling for red meat intake. It is also
possible that poultry and fish contain factors that may protect against colon
cancer. Poultry contains small amounts of nutrients such as selenium and calcium
that have been associated with lower risk of colorectal neoplasia,69-71 but it is a relatively
minor source of these nutrients. Fish is a primary source of omega-3 fatty
acids and high intake of fish or fish oil has been inversely associated with
colorectal cancer risk in some epidemiological studies.40,47,72 In
experimental studies, omega-3 fatty acids have been shown to inhibit tumor
growth and to modulate the expression of proinflammatory genes.73,74 However,
the poultry and fish consumed by CPS II Nutrition Cohort participants consisted
mostly of chicken.

Our findings add to the limited prospective data38,49,75 on
meat consumption in relation to rectal cancer. Consumption of red meat, as
reported in 1992/1993, was more strongly associated with rectal than colon
cancer in our study, as has been reported in some4,5,20,21 but
not all17,18,23,24,28,29 case-control
studies. One recent case-control study found no association between rectal
cancer and red meat, poultry and fish, or processed meat consumption but reported
increased risk associated with greater doneness of red meat among men.76 In our study, the positive association and significant
dose-response relationship was observed mostly with tumors of the rectosigmoid
junction rather than the rectum. Taken together with the higher risk of cancer
observed in the distal colon, our results suggest that tumors in the distal
portion of the large intestine may be particularly associated with meat consumption.
It is possible that concentration of stool in the distal portion of the large
intestine may contribute to higher cancer risk by increasing exposure to carcinogens
as a result of water resorption during transit through the large intestine.

Our study had several limitations in addition to the measurement error
inherent in studies based on FFQs.77 The 1982
questionnaire did not assess the number of servings of meat per day and could
not differentiate persons who ate multiple servings from those who ate meat
only once per day; we were also unable to estimate total energy intake from
the 1982 diet questionnaire. We had no information on meat cooking methods
to estimate exposure to heterocyclic amines or other specific carcinogens
produced from pyrolysis of meat78-82; our reliance on self-reported data on preference for doneness of meat was
likely a crude proxy of the relevant exposures. Although heterocyclic amines
are potent mutagens in the Ames assay and are carcinogenic in animal studies,
the impact of these compounds on colorectal carcinogenesis in humans is less
clear,81-83 primarily
due to the difficulties in measuring exposure and possible interactions between
meat and other dietary constituents or genetic susceptibility.9,84 We
had no information on family history of colorectal cancer from the 1992/1993
questionnaire to update this important variable, which could potentially modify
the association between meat intake and risk of colorectal cancer. No information
was collected on examination by sigmoidoscopy, colonoscopy, or fecal occult
blood test in either the 1982 or 1992/1993 questionnaires. However, in 1997,
persons who reported long-term high consumption of red meat were less likely
(23%) to have had endoscopy for screening than those persons who reported
long-term low intake of red meat (34%). It is difficult to predict the net
effect of endoscopy on colorectal cancer incidence. On the one hand, endoscopic
removal of precancerous lesions could contribute to lower risk; however, endoscopy
could accelerate the diagnosis of some tumors that might not otherwise have
been identified during the follow-up period.

The main strengths of this study are its size, the availability of dietary
and other exposure information collected prospectively from respondents at
2 time points, and information on major potential confounders. The sample
size allowed us to obtain stable estimates of risk and to show differences
by colorectal subsite. Our results demonstrate the potential value of examining
long-term meat consumption in assessing risk and strengthen the evidence that
prolonged high consumption of red and processed meat may increase the risk
of cancer in the distal portion of the large intestine.

Funding/Support: The American Cancer Society
(ACS) funds the creation, maintenance, and updating of the Cancer Prevention
Study II Nutrition Cohort. All of the authors were employed by either the
ACS or the National Cancer Institute (NCI) during the course of the study.
Dr Chao was supported by the ACS and Public Health Service grant K07CA75062
from the NCI, National Institutes of Health, Department of Health and Human
Services, until her relocation to Zambia in July 2004.

Role of the Sponsor: Staff in the Epidemiology
and Surveillance Research Department of ACS designed and conducted the study,
including collection, analysis, interpretation, and presentation of the manuscript.
No staff at ACS or NCI, other than study investigators, reviewed or approved
the manuscript.

Acknowledgment: We express sincere gratitude
to all CPS II Nutrition Cohort participants and to each member of the CPS
II Study Management Group.